4-Hydroxy-2-quinolinone-3-carboxylic acid esters

ABSTRACT

Disclosed are compounds which are 4-hydroxy-2-quinolinone-3-carboxylic acid esters, e.g., 1-methyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, useful as anti-allergic agents and intermediates for 1-alkyl-4-alkoxy-quinolin-2(1H)-ones, and prepared by reacting an isatoic anhydride with an alkali metal salt of a malonic ester.

This is a division of application Ser. No. 807,898 filed June 20, 1977now U.S. Pat. No. 4,190,659, which in turn is a continuation-in-part ofSer. No. 662,148, filed Feb. 27, 1976, now abandoned, which in turn is acontinuation-in-part of Ser. No. 557,984, filed Mar. 12, 1975, nowabandoned, which in turn is a division of Ser. No. 454,070, filed Mar.25, 1974, now abandoned which in turn is a continuation-in-part of Ser.No. 303,099, filed Nov. 2, 1972 and of Ser. No. 392,082, filed Aug. 27,1973, now both abandoned.

DISCLOSURE OF THE INVENTION

The present invention relates to chemical compounds and their use aspharmaceutical agents and intermediates, and more particularly tocompounds which are 4-hydroxy-2-quinolinone-3-carboxylic acid esterswhich are useful as anti-allergic agents and as intermediates for1-alkyl-4-alkoxyquinolin-2(1H)-ones.

In my earlier prior applications above-identified, there is disclosed,inter alia, compounds having CNS depressant activity and represented bythe following structural formula I: ##STR1## wherein

R^(o) is alkyl of 1 to 6 carbon atoms,

R is alkyl of 1 to 8 carbon atoms,

R' is hydrogen or alkyl of 1 to 6 carbon atoms, and

R" is hydrogen, halo of atomic weight of from 18 to 80, i.e., fluoro,chloro or bromo or alkoxy of 1 to 4 carbon atoms.

The compounds I may be prepared in a Step A reaction by reacting acompound of the formula II: ##STR2## wherein R^(o), R' and R" are asdefined and M is hydrogen or an alkali metal, with a compound of theformula III:

    RX                                                         III

wherein R is as defined and X is chloro, bromo or iodo or a radical ofthe formula IIIa:

    BO-                                                        IIIa

in which B is methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.

The preparation of compounds I by the reaction of Step A may be suitablycarried out at temperatures of from 0° C. to 120° C., preferably 10° C.to 40° C. The reaction may be carried out in absence of added solventwhen III is liquid but is preferably effected with an inert solvent ofconventional type such as dioxane, dimethylformamide anddimethylacetamide. The compounds of the formula II in which M is analkali metal are preferably employed and are formed in a conventionalmanner by reacting a compound II in which M is hydrogen with a strongbase such as an alkali metal hydride, an alkali metal hydroxide oralkali metal carbonate, preferably sodium hydride. When Step A iscarried out employing a compound II in which M is hydrogen it isdesirable to effect the reaction in the presence of strong base such asan alkali metal hydride, e.g., sodium hydride, or an alkali metalcarbonate, e.g., potassium carbonate, and preferably at temperatures offrom 10° C. to 80° C. The reaction product of the formula I may berecovered from the reaction mixture of Step A by working up byestablished procedures.

The compounds of the formula I may also be prepared in process B byreacting a compound of the formula IV: ##STR3## wherein R, R', R" and Mare as above defined, with a compound of the formula V:

    R.sup.o X                                                  V

wherein R^(o) and X are as defined above.

The preparation of compounds I by the reaction of process B may besuitably carried out at temperatures of from 0° C. to 120° C.,preferably 10° C. to 40° C. The reaction may be carried out in absenceof added solvent when V is liquid but is preferably effected with aninert solvent of conventional type such as dioxane, dimethylformamideand dimethylacetamide. The compounds of the formula IV in which M is analkali metal are preferably employed and are formed in a conventionalmanner by reacting a compound IV in which M is hydrogen with a strongbase such as an alkali metal hydride, an alkali metal hydroxide oralkali metal carbonate, preferably sodium hydride, at temperatures offrom 0° C. to 120° C., preferably 10° C. to 80° C. When process B iscarried out employing a compound IV in which M is hydrogen it iseffected in the presence of a strong base such as an alkali metalhydride or carbonate, e.g., sodium hydride or potassium carbonate, andat temperatures of from 0° C. to 120° C., preferably 10° C. to 80° C.The reaction product of the formula I may be recovered from the reactionmixture of process B by working up by established procedures.

The compounds of the formula I in which R and R^(o) are the same may bealso prepared in process C by reacting a compound of the formula VI:##STR4## wherein R', R" and M are as above defined, with a compound ofthe formula V, given above.

Process C is carried out analogously to processes A and B employing atleast about the theoretical amount of the compound of formula V tocomplete the reaction, i.e., at least 2 mols of compound V per mol ofcompound VI. When M is hydrogen it is preferable to employ temperaturesof from 10° C. to 80° C. The compounds of the formula VI in which M isan alkali metal are formed in a conventional manner employing at leastabout the theoretical amount of an alkali metal hydride or the like, andat temperatures of from 0° C. to 120° C., preferably 10° C. to 80° C. Ingeneral, it is preferred to employ an excess of both the compound V andthe base when preparing compounds I and an excess of alkali metalhydride or other suitable base when preparing the compounds of theformula VI in which M is an alkali metal.

The compounds of the formula II in which M is hydrogen are also eitherknown or may be prepared from known materials by known procedures. Forexample, in U.S. Pat. No. 3,133,928 said compounds are disclosed anddepicted in their alternative or tautomeric form having the structuralformula IIa: ##STR5## in which R^(o), R' and R: are as above defined.

A procedure discovered for the preparation of the compounds of theformula II and preferred for preparation of certain such compounds, forexample, those in which R' is alkyl, involves the reaction of a compoundof the formula VII: ##STR6## in which R^(o) and R: are as above defined,with a compound of the formula VIII: ##STR7## in which R' is as abovedefined and each R''' is alkyl of 1 to 4 carbon atoms.

The reaction of a compound VII with a compound VIII may be convenientlycarried out in the presence or absence of a solvent at temperatures inthe range of from 120° C. to 280° C., preferably in the absence of addedsolvents at temperatures of from 150° C. to 280° C., more preferably200° C. to 250° C. Reaction times may vary fairly widely from say 1 hourto 50 hours, more typically 5 to 30 hours. The reaction of a compoundVIII in which each R''' is ethyl and R' is butyl with a compound VII inwhich R' is methyl and R" is hydrogen has been effected satisfactorilyat 220° C. over an 18 hour period. In general, the preferred compoundsof the formula VIII are those in which each R''' is ethyl. The reactionproduct of the formula II may be recovered from the reaction mixture byworking up by established procedures. The compounds of the formula VIIand VIII are either known or may be prepared from known materials byconventional procedures.

The compounds of the formula IV employed in process B may be prepared bysubjecting a compound of the formula IVa ##STR8## wherein R', R" and Mare as defined, to reaction analogously to that of processes A, B and Cas described above using controls to avoid any substantial alkylation ofthe 1-position of said compound IVa. Such control may be effected in thereaction in which the strong base is employed by:

(1) employing no more than about the theoretical amound of sodiumhydride or other base used in the reaction, or (2), by employing a baseto compound IVa mol ratio of about 1.5 to 1 or more and temperatureswithin the range of from 0° C. to 40° C., preferably 15° C. to 30° C.,with the time and temperature of the reaction being regulated inverselywith the mol ratio of base to compound IVa. In general, the mol ratio ofbase relative to the compound IVa is desirably no more than 3.1.Preferably, the ratio is about 1:1 and the temperature from 15° C. to30° C.

The compound of the formulae IV and IVa in which M is hydrogen areeither known or may be prepared from material by the known procedures.

The compound of the formula IIaa: ##STR9## in which R^(o) and R" are asdefined above, may also be produced by hydrolysis and decarboxylation ofa compound of formula IX: ##STR10## in which R^(o) and R" are as definedabove, and

R₉ is alkyl of 1 to 4 carbon atoms.

The hydrolysis may suitably be effected in the presence of a strongbase, e.g., sodium hydroxide in an aqueous medium, e.g., water oraqueous ethanol, and at a temperature of from 40° C. to 150° C.,preferably 80° C. to 120° C. The mixture may suitably then be acidifiedwith, for example hydrochloric acid, and at a temperature of from 0° C.to 150° C., preferably 10° C. to 50° C., whereupon the free aciddecarboxylates to yield the desired product. Where R₉ signifies t-butyl,the process is more suitably effected at a temperature of from 80° C. to250° C., preferably 130° C. to 200° C. and in the presence or absence ofan added solvent, such as a hydrocarbon or chlorinated hydrocarbonsolvent.

The resulting compounds of formula IIaa may be isolated and purifiedusing conventional techniques.

The compounds of formula IX are novel and may be produced by reacting acompound of formula X: ##STR11## in which R^(o) and R" are as definedabove, with a compound of formula XI: ##STR12## in which

R₉ is as defined above, and

M' signifies an alkali metal.

The process is suitably carried out in an inert organic solvent, e.g.,dimethyl acetamide, and at a temperature of from 0° C. to 150° C.,preferably 60° C. to 120° C. followed, if necessary, by neutral or acidhydrolysis to obtain the desired compound IX from any 4-alkali metalsalt thereof initially produced.

The compounds of formula XI may be produced from the correspondingdialkyl malonates by reaction with a strong alkali metal base, e.g.,sodium hydride, and in an inert organic solvent, e.g., dimethylacetamide.

The resulting compounds of formula IX may be isolated and purified usingconventional techniques.

The compounds of formula X are either known or may be produced inconventional manner from available materials.

The compounds of the formula I are useful because they possesspharmacological activity in animals. In general, the compounds I effecta depression of the central nervous system and are useful as minortranquillizers as indicated by a CNS depressant (docility) effect inbehavior tests in mice (10-200 mg./kg.) and/or by an inhibition ofchemically induced seizures in mice on intraperitoneal administration(10-200 mg./kg.) using 50 mg./kg. of N-sulfamoylazepine to induceseizures. Many of the compounds I such as those of Examples 4a, 4b, 4r,4d, 4e and 4f hereinafter, also effect a reinduction of hexobarbitalanesthesia in mice (10-200 mg./kg. Certain of the compounds I such asthose of Examples 1, 3 and 4g hereinafter, in addition to all the aboveindications, provide responses indicative of a spectrum of tranquillizeractivity having a muscle relaxant component as indicated by aneurological deficit and muscle relaxation in the "rotarod test" in miceon administration intraperitoneally (10-150 mg./kg.) essentiallyaccording to the method of Dunham et al., J. Am. Pharm. Assoc. 45:208,1957, and/or a depression of spiral reflexes in anesthetized male catson intravenous administration (0.5-20 mg./kg.) as determined bymeasuring flexor and patellar responses using force displacementtransducers. The preferred compound which is1-methyl-4-butoxyquinolin-2(1H)-one also inhibits aggression in theshocked-induced fighting mice test on administration intraperitoneally(20-100 mg./kg.).

For the above-mentioned usage, the dosage administered will of coursevary depending upon known factors such as the compound used, mode ofadministration and therapy desired. However, in general, satisfactoryresults for the above usage may be obtained on administration of acompound I at a daily dose of from about 1.0 to 200 milligrams perkilogram of body weight, preferably given orally and in divided doses 2to 4 times a day or in sustained release form. For larger mammals theadministration of from 60 milligrams to 2000 milligrams of the compoundper day provides satisfactory results and dosage forms suitable forinternal administration comprise from about 15 milligrams to about 1000milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier.

It has now been found that the compounds IX, above disclosed, form apart of a larger series of compounds having pharmacological activity, inparticular anti-allergic activity, said series being representedstructurally by the formula IX_(p) : ##STR13## wherein R₉ is as abovedefined, and wherein

R_(p) ^(o) is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6carbon atoms, alkynyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6carbon atoms, cycloalkylalkyl in which the cycloalkyl is of 3 to 6carbon atoms and the alkyl portion is of 1 or 2 carbon atoms, or##STR14##

M_(p) is hydrogen or a pharmaceutically acceptable cation,

n is 0 or 1,

Y and Y' are independently hydrogen, halo of atomic weight of from 18 to80, i.e., fluoro, chloro or bromo, alkyl of 1 to 3 carbon atoms, alkoxyof 1 to 3 carbon atoms, trifluoromethyl or nitro, with the proviso thatonly one of Y and Y' can be from the group consisting of nitro andtrifluoromethyl, and

R_(p) and R_(p) ' are independently hydrogen, halo of atomic weight offrom 18 to 80, i.e., fluoro, chloro or bromo, alkyl of 1 to 4 carbonatoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl, or R_(p)and R_(p) ' together form 6,7-methylenedioxy, with the proviso that onlyone of R_(p) and R_(p) ' can be from the group consisting of nitro andtrifluoromethyl,

with the further proviso that the unsaturation in any alkenyl or alkynylis on other than the alpha carbon atom.

The compounds of the IX_(p) in which M is hydrogen may be prepared byreacting a compound of the formula X_(p) : ##STR15## wherein R_(p) ^(o),R_(p) and R_(p) ' are as above defined, with a compound of the formulaXI: ##STR16## wherein R₉ and M' are as above defined, in the manner andunder the condition hereinbefore described for the preparation ofcompounds IX from compound X and XI.

The comounds IX_(p) in which M_(p) is a pharmaceutically acceptablecation, e.g., lithium, sodium, potassium, ammonium, etc., may beprepared from the compound IX_(p) in which M_(p) is hydrogen byprocedures well known in the art, e.g., by treating with a base such asdilute aqueous sodium hydroxide in a water miscible solvent.

The compounds of the formula X_(p) and XI employed in the preparation ofcompound IX_(p) are either known or may be produced in conventionalmanner from known materials, or as described herein.

The compound 4-methoxy-2-quinolinone-3-carboxylic acid ethyl ester isknown from McCorkindale, Tetrahedron, 1961, Vol. 14, pp. 223-229, but tomy knowledge has not been associated with any useful pharmacologicalactivity. Also, Coutts et al., J. Chem. Soc. 1962, 2518-21, disclose thecompound 4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, butwithout the association of any useful pharmacological activity.Similarly, Brown, Australian J. Chem. 8, 121-4 (1955), disclose variousN-unsubstituted polyalkoxy-4-hydroxy-2-quinolinone-3-carboxylic acidesters, eg. 6,7-dimethoxy-4-hydroxy-2-quinolinone-carboxylic acid methylester.

In addition to the novel compounds IX which also have particular use asintermediates for the compounds I, novel subgroupings within the scopeof the compounds IX_(p) provided by this invention and disclosed as ofparticular interest as anti-allergic agents in my aforementioned Ser.No. 662,148, now abandoned, are those in which R_(p) and R_(p) ' areother than methylenedioxy and R_(p) ^(o) is: (a) alkenyl of 3 to 6carbon atoms; (b) alkynyl of 3 to 6 carbon atoms; (c) cycloalkyl of 3 to6 carbon atoms; (d) cycloalkylalkyl in which the cycloalkyl portion isof 3 to 6 carbon atoms and the alkyl portion is 1 or 2 carbon atoms; (e)Y,Y'-substituted phenyl wherein Y and Y' are as above defined: and (f)Y,Y'-substituted benzyl wherein Y and Y' are as above defined. Also ofparticular interest are the compounds of the formula IX_(p) in whichR_(p) ^(o) is hydrogen, R_(p) is hydrogen, fluoro, chloro, bromo, alkylof 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms and R_(p) ' isfluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4carbon atoms. Similarly of particular interest are the compounds IX_(p)in which R_(p) ^(o) is alkyl and R_(p) and R_(p) ' are independentlyhydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms or alkoxyof 1 to 4 carbon atoms.

Generally preferred compounds IX_(p) (R_(p) and R_(p) ' being other thanmethylenedioxy) are those having one or both, particularly both, of thefeatures: (a) R_(p) ^(o) being hydrogen, alkyl or alkenyl, morepreferably alkyl or alkenyl, and most preferably allyl; and (b) R_(p)and R_(p) ' both being alkoxy, more preferably representing6,7-dialkoxy, and most preferably representing 6,7-dimethoxy.Accordingly, representative additional novel subgroupings provided bythe invention include those in which R_(p) ^(o) is alkyl or alkenyl,particularly allyl, and R_(p) and R_(p) ' represent dialkoxy, morepreferably 6,7-dialkoxy, and more preferably 6,7-dimethoxy.

further novel subgrouping provided by this invention are those compoundsIX_(p) in which R_(p) and R_(p) ' together form 6,7-methylenedioxy, andthe preferred significances of R_(p) ^(o) in such compounds are alkyland alkenyl, more preferably allyl.

The compounds of formula IX_(p) are useful because they possesspharmacological activity in animals. In particular they possess disodiumchromoglycate (DSCG)-like activity, in particular histamine releaseinhibiting activity, and are therefore useful in the treatment ofallergic conditions, such as allergic asthma, as indicated in thepassive cutaneous anaphylaxis test in the rat. Female rats (180-200 g)are sensitised by subcutaneous administration of 1 mg. of egg albumin(Merck Nr. 967) and 200 mg of Al(OH)₃ dissolved in 1 ml of physiologicalsaline and 0.5 ml of Haemophiluspertussis vaccine (Schweizerisches Serumand Impfinstitut, Bern; Nr. 115 325; 4×10¹⁰ organism/ml)intraperitoneally. Fourteen days later, the animals are exsanguinated,the blood centrifuged, the serum collected and deep frozen. The serumthus obtained (anti-serum) is injected intradermally (0.1 ml of a 1:200diluted serum per injection site) at four sites on the backs ofuntreated, female rats. Twenty-four hours later each rat is administered0.1 to 5.6 mg/kg i.v. or 0.1 to 100 mg/kg p.o. of the test compound, andeither immediately or 5 to 30 minutes afterwards, in the case ofintravenous administration, or 15 or 60 minutes afterwards, in the caseof oral administration, afterwards egg albumin (5 mg/ml i.v.) dissolvedin physiological saline containing 0.25% Evans Blue dye (Merck Nr.3169). The egg albumin elicits a cutaneous anaphylactic reaction, theintensity of which is proportional to the extent to which the Evans Bluedye diffuses into the tissue surrounding each of the four sensitisationsites. Thirty minutes after the administration of the egg albumin, therats are killed with ether, the underside of the skin of the back ofeach animal is exposed and the diameter of the areas of blue dyesurrounding each of the four sensitisation sites are measured. Each doseof test compounds is investigated in between four and six rats and themean diameter compared with the mean value obtained in foursolvent-treated control rats.

The percentage inhibition is taken as the percentage of the meandiameter in the test animals relative to the mean diameter in thecontrols.

The DSCG-like activity, in particular histamine release inhibitingactivity, can be confirmed by inhibition of histamine release in the ratperitoneal mast cell test, basically as described by Kusner et al., J.Pharmacol. Exp. Therap. 184, 41-46 (1973), with the followingmodification: after sedimentation of the mast cells by centrifugation at350×g and 4° C., the sediments are taken up in 1 ml of Hank's balancedsalt solution (HBSS) (buffered to a pH of 6.9) and pooled. The resultingsuspension is centrifuged, washed again with HBSS and sedimented. Thethus purified mast cells are prepared as 2 ml suspensions in HBSS. Tothese are added either 2 ml of HBSS, to determine the spontaneoushistamine release, or 2 ml of HBSS and 2.24 μg of compound 48/80(N-methylhomoanisylamineformaldehyde condensate; a histamine liberatorfrom Burroughs Wellcome and Co. Inc., Tuckahoe, N.Y. USA), to determinethe 48/80 induced histamine release, or 2 ml of HBSS with 2.24 μg of48/80 and from 18 to 180 μg/ml of the test compound, to determine the48/80 induced histamine release in the presence of the test compound.

The 48/80 induced histamine release minus the spontaneous histaminerelease is taken as 100% histamine release. The 48/80 induced histaminerelease in the presence of the test compound minus the spontaneoushistamine release is then compared with the 100% value to determine thepercentage inhibition by the test compound. [The histamine determinationis effected in conventional manner, for example, as described in theabove-mentioned Kuzner et al. article, or in Kusner and Herzig, Advancesin Automated Analysis, 429 (1971)].

For the above-mentioned anti-allergic use, the dosage administered will,of course, vary depending on the compound employed, mode ofadministration and treatment desired. However, satisfactory results aregenerally obtained on the administration of compounds IX_(p) at a dailydosage of from about 0.3 to 100 mg/kg of animal body weight,conveniently given in divided doses two to four times daily, or insustained release form. For he larger mammals, the total daily dosage isin the range of from about 20 to 800 mg of the compound admixed with asolid or liquid pharmaceutical carrier, and divided dosage formscomprise 5 to 400 milligrams of the compound in admixture with a solidor liquid pharmaceutical carrier. As will be appreciated by thoseskilled in the art, the treatment of allergic conditions according tothe invention is based on histamine release inhibition activity and istherefore essentially symptomatic. The ability to employ such compoundsin the prophylactic treatment of such allergic conditions (as evidentfrom its DSCG-like activity) is a desirable features of such compounds.However, the good oral activity relative to DSCG is a further feature.

A representative formulation for administration 2 to 4 times a day forprophylactic treatment of allergic asthma is a capsule prepared bystandard techniques to contain the following:

    ______________________________________                                        Ingredient              Weight (mg)                                           ______________________________________                                        N-allyl-6,7-dimethoxy-4-hydroxy-2-                                            quinolinone-3-carvoxylic acid ethyl ester                                                             10                                                    Kaolin                  210                                                   ______________________________________                                    

The following examples are given for purposes of illustration only.

EXAMPLE 1 1-Methyl-4-butoxyquinolin-2(1H)-one ##STR17##

To a solution of 10.0 g. of 1-methyl-4-hydroxyquinolin-2(1H)-one in 150ml. of dimethylformamide is added 2.4 g. of pentane washed with sodiumhydride and the resulting mixture stirred for 2 hours at roomtemperature. There is then added 10.6 g. of n-butyl iodide and theresulting mixture is stirred for 24 hours at room temperature. Thereaction mixture is then poured onto 1.3 liters of cold water, extractedwith ethyl acetate, washed 3 times with water, dried, charcoaled,filtered and evaporated in vacuo. The resulting oil is dissolved in 120ml. of ether and cooled in an acetone/dry ice bath to crystallize solidswhich are filtered off and washed with cold ether to obtain1-methyl-4-butoxyquinolin-2(1H)-one, m.p. 77°-80° C.

EXAMPLE 2 1-Methyl-4-ethoxyquinolin-2(1H)-one (Process 2)

Step A: Preparation of 4-ethoxyquinolin-2(1H)-one.

To a suspension of 6 g. of quinoline-2,4-dione in 50 ml. ofdimethylacetamide is added 1.6 g. of sodium hydride (56% in mineral oil,pentane washed). The mixture is then stirred at room temperature for 90minutes and 6 g. of ethyliodide is added and the resulting mixture isheated briefly at 35° C. followed by stirring at ambient temperature for18 hours. The precipitate which forms is recovered by filtering and thefiltrate is poured into 200 ml. of water and the resulting precipitatealso recovered by filtering and dried. The two filter cakes aboveobtained are combined and crystallized from methanol to obtain4-ethoxyquinolin-2(1H)-one, m.p. 223°-226° C.

Step B: Preparation of 1-methyl-4-ethoxyquinolin-2(1H)-one.

To a suspension of 1.9 g. of 4-ethoxyquinolin-2(1H)-one in 40 ml. ofdimethylacetamide is added 0.42 g. of sodium hydride (56% in mineraloil, pentane washed), and the resulting mixture is heated at 60° C. forone hour. The mixture is filtered (while excluding moisture), cooled andthere is then added 1.5 g. of methyliodide followed by stirring for 2hours at ambient temperatures. The resulting mixture is poured into 200ml. of cold water and the resulting slurry extracted 3 times each with100 ml. of ethyl acetate. The combined organic extracts are washed withwater and saturated sodium chloride solution, dried and evaporated invacuo. The residue is crystallized from ether to obtain1-methyl-4-ethoxyquinolin-2(1H)-one, m.p. 80°-82° C.

EXAMPLE 3 Preparation by Process 3 of1-Butyl-4-butoxyquinolin-2(1H)-one.

To a suspension of 10 g. of 4-hydroxyquinolin-2(1H)-one in 100 ml. ofdimethylacetamide is added in portions 5.4 g. of sodium hydride (57% inmineral oil, pentane washed) and the mixture then stirred for one hourat room temperature. There is then added dropwise 24 g. of n-butyliodide and the mixture is stirred for 3 hours at ambient temperatures.The resulting mixture is poured into water, extracted with ethylacetate, the organic phase washed with water and saturated sodiumchloride solution, dried and evaporated in vacuo. The residue isdissolved in chloroform and subjected to column chromatography (silicagel) and thin layer chromatography employing a s-lution of 5% ethanoland 95% chloroform as solvent. The product (R_(f) 0.75) obtainedsubsequent to the first eluted product (R_(f) 0.85) is purified bydistillation under high vacuum (142°-148° C. @ 0.1 mm/Hg.) andcrystallized from ether to obtain 1-butyl-4-4butoxyquinolin-2(1H)-one,m.p. 50°-52° C.

EXAMPLE 4

Following the procedure of Examples 1 and 2, the following additionalcompounds of the invention are prepared:

(a) 1-methyl-4-methoxyquinolin-2(1H)-one, m.p. 95°-100° C.

(b) 1-methyl-4-hexoxyquinolin-2(1H)-one, m.p. 66°-69° C.

(c) 1-methyl-4-sec-butoxyquinolin-2(1H)-one, as an oil.

(d) 1-methyl-4-isobutoxyquinolin-2(1H)-one, m.p. 85°-87° C.

(e) 1-butyl-4-hexoxyquinolin-2(1H)-one, m.p. 45°-48° C.

(f) 1-ethyl-4-hexoxyquinolin-2(1H)-one, m.p. 56°-58° C.

(g) 1-methyl-4-pentoxyquinolin-2(1H)-one, m.p. 62°-65° C.

(h) 1-methyl-4-butoxy-3-butylquinolin-2(1H)-one, as an oil.

(i) 1-methyl-2-ethoxyquinolin-2(1H)-one, m.p. 78°-81° C.

(j) 1-butyl-4-pentoxyquinolin-2(1H)-one, m.p. 45°-48° C.

(k) 1-methyl-4-propoxyquinolin-2(1H)-one, m.p. 83°-85° C.

(l) 7-chloro-1-butyl-4-butoxyquinolin-2(1H)-one, m.p. 98°-100° C.

(m) 1-hexyl-4-hexoxyquinolin-2(1H)-one, m.p. 54°-56° C.

(n) 6-methoxy-1-methyl-4-butoxyquinolin-2(1H)-one, m.p. 99°-102° C.

(o) 6-chloro-1-methyl-4-butoxyquinolin-2(1H)-one, m.p. 140°-143° C.

(p) 7-chloro-1-butyl-4-hexoxyquinolin-2(1H)-one, m.p. 95°-98° C.

(q) 1-methyl-4-heptoxyquinolin-2(1H)-one, m.p. 39°-41° C.

(r) 1-methyl-4(2-pentyl)-quinolin-2(1H)-one, as an oil.

(s) 1-methyl-4-octoxyquinolin-2(1H)-one, m.p. 67°-69° C.

EXAMPLE 5

Following the procedure of Example 3, the following compounds areprepared:

(a) 1-methyl-4-methoxyquinolin-2(1H)-one, m.p. 95°-100° C.

(b) 7-chloro-1-butyl-4-butoxyquinolin-2(1H)-one, m.p. 98°-100° C.

(c) 1-hexyl-4-hexoxyquinolin-2(1H)-one, m.p. 54°-56° C.

EXAMPLE 6 N-Butyl-4-butoxyquinolin-2(1H)-one

(a) N-Butyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.

A solution of 25 g. of N-butylisatoic anhydride in 100 ml. ofdimethylacetamide is added, dropwise, to a solution of sodio-diethylmalonate (prepard by reacting 20 g. of diethyl malonate in 100 ml. ofdimethylacetamide with 5.3 g. of sodium hydride (57% in mineraloil)--first at room temperature and then briefly at 120° C.). Theresulting mixture is heated at 120° C. for 16 hours. The dimethylacetamide is evaporated off, water is added and the mixture extractedwith ethyl acetate. The organic phase is extracted twice with water andthen with saturated sodium chloride solution, followed by drying oversodium sulphate and evaporation in vacuo. The residue is dissolved in150 ml. of methylene chloride and 100 ml. of diethyl ether is added. Theprecipitate is filtered off and the filtrate is evaporated and elutedthrough a silica column with a mixture of 98% chloroform and 2% methanolto yield an oil which crystallizes on standing. The crystals arefiltered off, after addition of pentane to yield the heading compound,m.p. 54°-55° C.

(b) N-Butyl-4-hydroxyquinoline-2(1H)-one.

8.8 g. of N-butyl-4-hydroxy-2-quinolin-3-carboxylic acid ethyl ester isrefluxed with 100 ml. of 2 N sodium hydroxide solution for 24 hours. Theresulting solution is heated with charcoal, acidified with 2 N HCl andthe precipitate filtered off, washed with water dried and recrystallizedfrom methanol to obtain the heading compound, m.p. 211°-213° C.

(c) 1-Butyl-4-butoxyquinolin-2(1H)-one.

In manner analogous to Example 1, employing an approximately equivalentamount of the compound of step (b), above, in place of the1-methyl-4-hydroxyquinolin-2(1H)-one, the heading compound, m.p. 50°-52°C. is obtained.

EXAMPLE 7

In manner analogous to Example 6a, employing appropriate startingmaterials in approximately equivalent amounts, the following compoundsmay be obtained:

(A) N-hexyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p.64°-66° C.,

(B) N-ethyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p.68°-71° C.,

(C) N-butyl-7-chloro-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester, m.p. 54°-55° C.,

(D) N-methyl-6-methoxy-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester, m.p. 130° to 133° C.

(E) N-methyl-6-chloro-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester, m.p. 132°-135° C.

(F) N-methyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p.100°-102° C.

(G) 6-methyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.

(H) N-allyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p.88°-91° C.

(I) N-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester, m.p. 165°-166° C.

(J) 6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.

(K) 6-chloro-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.

(L) N-cyclopentyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.

(M) N-cyclopropylmethyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester.

(N) N-(o-nitrobenzyl)-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester, m.p. 148°-151° C.

(O) N-propargyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester,m.p. 171°-174° C.

(P) N-(p-fluorobenzyl)-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester, 126°-129° C.

(Q) N-phenyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester,180°-183° C.

(R) N-methyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester, m.p. 216°-219° C.

(S) N-(2-butynyl)-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylicacid ethyl ester, m.p. 244°-246° C.

(T)N-(2-methyl-3-propenyl)-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylicacid ethyl ester, m.p. 163°-164° C.

(U) N-propyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester, m.p. 166°-169° C.

(V)N-cyclopropylmethyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylicacid ethyl ester, m.p. 176°-178° C.

(W) N-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acidn-butyl ester, m.p. 144°-147° C.

(X) N-(2-butenyl)-6,7-methoxy-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester, m.p. 151°-154° C.

(Y) N-(3-butenyl)-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylicacid ethyl ester, m.p. 193°-195° C.

(Z) N-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acidt-butyl ester, m.p. 142°-144° C.

(Z-1) N-allyl-6,7-methylenedioxy-2-quinolinone-4-hydroxy-3-carboxylicacid ethyl ester, m.p. 147°-149° C.

(Z-2) N-allyl-6,7-dichloro-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester, m.p. 146°-148° C.

(Z-3) N-allyl-6-methoxy-7-ethyl-4-hydroxy-2-quinolinone-3-carboxylicacid ethyl ester.

(Z-4) N-allyl-6-methoxy-7-methyl-4-hydroxy-2-quinolinone-3-carboxylicacid ethyl ester.

(Z-5) N-allyl-6,7-dimethyl-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester.

Pharmaceutical compositions provided by the invention and useful fortreating allergic conditions due to histamine release contain a compoundof the formula IX_(p) as active ingredient and one or more conventionalpharmaceutically acceptable carriers, and such other conventionaladjuvants as may be desired or necessary. Such compositions may be inconventional orally administerable forms such as tablets, capsules,granules, dispersible powders, elixirs, syrups, suspensions and the likeor in conventional parenterally administerable forms such as aninjectable sterile solution, suspension or the like, e.g., a sterileinjectable aqueous suspension. Such compositions including applicableunit dosage forms thereof may be prepared according to any method knownin the art for the manufacture of pharmaceutical compositions. Thecompounds may also be administered by inhalation therapy techniques incompositions conventionally prepared and adapted for such procedures. Ingeneral, the compositions of the invention adapted for either oral,inhalation or parenteral administration may contain from 1% to 90% bytotal weight of active ingredient in combination with the carrier, moreusually 3% to 70%. The preferred unit dosage forms are the essentiallysolid forms adapted for oral administration, e.g., tablets or capsules.

Another subgrouping of the compounds IX_(p) of interest are those inwhich R_(p) ^(o) is allyl, R_(p) is alkyl of 1 to 4 carbon atoms in the7-position, preferably methyl or ethyl, and R_(p) ' is alkoxy of 1 or 2carbon atoms in the 6-position, preferably methoxy.

What is claimed is:
 1. A compound of the formula: ##STR18## wherein R₉is alkyl of 1 to 4 carbon atoms, wherein R_(p) ^(o) is alkenyl of 3 to 6carbon atoms, alkynyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6carbon atoms, cycloalkylalkyl in which the cycloalkyl is of 3 to 6carbon atoms and the alkyl portion is of 1 or 2 carbon atoms, or##STR19## M_(p) is hydrogen or a pharmaceutically acceptable cation, nis 0 or 1,Y and Y' are independently hydrogen, fluoro, chloro, bromo,alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,trifluoromethyl or nitro with the proviso that only one of Y and Y' canbe from the group of nitro and trifluoromethyl, and R_(p) and R_(p) 'are independently hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl,with the proviso that only one of R_(p) and R_(p) ' can be from thegroup consisting of nitro and trifluoromethyl,with the further provisothat the unsaturation in any alkenyl or alkynyl is on other than thealpha carbon atom.
 2. A compound of claim 1 in which M_(p) is hydrogen.3. A compound of claim 1 in which R_(p) ^(o) is alkenyl.
 4. A compoundof claim 1 in which R_(p) ^(o) is alkynyl.
 5. A compound of claim 1 inwhich R_(p) ^(o) is cycloalkyl.
 6. A compound of claim 1 in which R_(p)^(o) is cycloalkylalkyl.
 7. A compound of claim 1 in which R_(p) ^(o) is##STR20##
 8. A compound of claim 7 in which n is
 0. 9. A compound ofclaim 7 in which n is
 1. 10. A compound of claim 1 in which R_(p) andR_(p) ' are each alkoxy of 1 to 4 carbon atoms.
 11. A compound of claim10 in which R_(p) and R_(p) ' represent 6,7-dialkoxy.
 12. A compound ofclaim 11 in which R_(p) and R_(p) ' represent 6,7-dimethoxy.
 13. Acompound of claim 12 in which R_(p) ^(o) is allyl.
 14. The compound ofclaim 3 which is N-allyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester.
 15. The compound of claim 13 which isN-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester.
 16. The compound of claim 9 which isN-(p-fluorobenzyl)-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester.
 17. The compound of claim 5 which isN-cyclopentyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester. 18.The compound of claim 6 which isN-cyclopropylmethyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester.
 19. The compound of claim 4 which isN-propargyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester. 20.The compound of claim 8 which isN-phenyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.
 21. Acompound of the formula: ##STR21## wherein R^(o) is alkyl of 1 to 6carbon atoms,R" is hydrogen, fluoro, chloro, bromo or alkoxy of 1 to 4carbon atoms, and R₉ is alkyl of 1 to 4 carbon atoms.
 22. The compoundof claim 21 which is N-hexyl-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester.
 23. The compound of claim 21 which isN-ethyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.
 24. Thecompound of claim 21 which isN-butyl-7-chloro-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.25. The compound of claim 21 which isN-methyl-6-methoxy-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester.
 26. The compound of claim 21 which isN-methyl-6-chloro-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester.27. A compound of the formula: ##STR22## wherein R₉ is alkyl of 1 to 4carbon atoms, wherein R_(p) ^(o) is alkyl of 1 to 6 carbon atoms,M_(p)is hydrogen or a pharmaceutically acceptable cation, and R_(p) and R_(p)' are independently alkoxy of 1 to 4 carbon atoms.
 28. A compound ofclaim 27 in which R_(p) and R_(p) ' represent 6,7-dialkoxy.
 29. Acompound of claim 28 in which R_(p) and R_(p) ' represent 6,7-dimethoxy.30. A compound of claim 29 in which R_(p) ^(o) is methyl.
 31. Thecompound of claim 30 which isN-methyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid ethylester.
 32. A compound of the formula: ##STR23## wherein R₉ is alkyl of 1to 4 carbon atoms, wherein R_(p) ^(o) is hydrogen, alkyl of 1 to 6carbon atoms, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which thecycloalkyl is of 3 to 6 carbon atoms and the alkyl portion is of 1 or 2carbon atoms, or ##STR24## M_(p) is hydrogen or a pharmaceuticallyacceptable cation, n is 0 or 1, andY and Y' are independently hydrogen,fluoro, chloro, bromo, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3carbon atoms, trifluoromethyl or nitro, with the proviso that only oneof Y and Y' can be from the group consisting of nitro andtrifluoromethyl,with the further proviso that the unsaturation in anyalkenyl or alkynyl is on other than the alpha carbon atom.
 33. Acompound of claim 32 in which R_(p) ^(o) is alkyl.
 34. A compound ofclaim 32 in which R_(p) ^(o) is alkenyl.
 35. A compound of claim 34 inwhich R_(p) ^(o) is allyl.
 36. The compound of claim 35 which isN-allyl-6,7-methylenedioxy-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester.
 37. The compound of claim 13 which isN-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid n-butylester.
 38. The compound of claim 13 which isN-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid t-butylester.
 39. A compound of claim 3 in which R_(p) ^(o) is allyl.
 40. Acompound of claim 39 in which R_(p) is alkyl of 1 to 4 carbon atoms inthe 7-position and R_(p) ' is alkoxy of 1 to 2 carbon atoms in the b6-position.
 41. The compound of claim 40 which isN-allyl-6-methoxy-7-ethyl-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester.
 42. The compound of claim 40 which isN-allyl-6-methoxy-7-methyl-4-hydroxy-2-quinolinone-3-carboxylic acidethyl ester.